1. Field of the Invention
The invention described herein relates generally to the field of glaucoma therapy. In particular the invention relates to the treatment of glaucoma and ocular hypertension by use of a combination of at least one compound chosen from brimonidine and its derivatives, and at least one prostaglandin or derivative.
2. Background of the Art
Glaucoma is an ocular disorder associated with elevated intraocular pressure (IOP) which is too high for normal ocular physiology and may result in irreversible loss of visual function. Owing to the progressive nature of glaucoma, the disease may begin with elevated IOP, progress through loss of visual field and eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest stage of glaucoma.
Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory. Indeed, for a long period of time few advances were made in the treatment of glaucoma since pilocarpine and physostigmine were introduced. Only relatively recently have clinicians noted that many .beta.-adrenergic blocking agents are effective in reducing intraocular pressure, however, they also have other characteristics, e.g. membrane stabilizing activity, that are not acceptable for chronic ocular use. (S)-1-tert-Butylamino-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propan ol (also known as timolol), a .beta.-adrenergic blocking agent, was found to reduce intraocular pressure and to be devoid of many unwanted side effects associated with pilocarpine and, in addition, to possess advantages over many other .beta.-adrenergic blocking agents, e.g., to be devoid of local anesthetic properties, to have a long duration of activity, and to display minimal tolerance. A decrease in aqueous formation by the ciliary processes is thought to be the mechanism of action of beta-adrenoceptor antagonists, but the physiological basis for this action has not been clearly demonstrated. A newer beta-blocker, betaxolol, has relatively selective .beta..sub.1 blocking activity.
Standard treatment modalities include parasympathomimetic agents such as pilocarpine, carbachol, and phospholine iodide, which lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork. A newer form of pilocarpine as a gel produces a longer action. Adrenergic agonist medications, such as epinephrine (adrenaline) and its pro drug, dipivefrine (dipivalyl epinephrine), function by increasing uveoscleral outflow and trabecular outflow facility.
Certain members of the class of compounds known as alpha.sub.2 adrenergics have also been found useful in the treatment of glaucoma. Members of this class of compounds include clonidine and apraclonidine (aplonidine, ALO 2145), which has been released for clinical use. Apraclonidine hydrochloride is a derivative of clonidine hydrochloride, an alpha.sub.2 adrenergic agonist. Clonidine has previously been shown to lower IOP significantly, but has the potential to produce marked lowering of both systolic and diastolic blood pressures. Its major ocular effect appears to be a decrease in aqueous production. The structural modification to apraclonidine decreases corneal absorption and the drug's ability to cross the blood-brain barrier, minimizing the risk of centrally mediated cardiovascular side effects. Apraclonidine may also influence secondary avenues of aqueous outflow, such as uveoscleral outflow, and may also affect conjunctival and episcleral vascular flow. Another .alpha..sub.2 receptor agonist currently in clinical trials for use in treating glaucoma and elevated IOP is brimonidine (UK 14304-18). Disclosures of this family of compounds and methods of using same are made in (a) U.S. Pat. No. 3,890,319, (b) U.S. Pat. No. 4,029,792 and (c) U.S. Pat. No. 5,856,329, the entire contents of which are incorporated herein by reference.
Another class of agents, referred to as carbonic anhydrase inhibitors, block or impede aqueous inflow into the anterior chamber by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by oral, intravenous or other systemic routes, they thereby have the distinct disadvantage of inhibiting carbonic anhydrase throughout the entire body. Such gross disruption of a basic enzyme system is justified only during an acute attack of alarmingly elevated intraocular pressure, or when no other agent is effective. Almost 50% of patients taking these medications are unable to tolerate them because of their adverse effects, and there is thus much interest in the development of a topical carbonic anhydrase inhibitor with the potential for fewer adverse effects. MK 507 is the most recent and most potent compound in the series of topically active carbonic anhydrase inhibitors. It produces a mean decrease in IOP of 25% for as long as 12 hours. Adverse effects include blanching of the conjunctiva, minimal mydriasis and eyelid retraction. This drug has been approved in the US for use in prevention of elevated IOP after argon laser trabeculoplasty and iridotomy, and has potential uses in preventing an IOP rise after YAG laser posterior capsulotomy and cataract surgery in patients already on other anti-glaucoma medications. For a recent review of therapeutics in the treatment of glaucoma see Hurvitz L. M.; Kaufman P. L.; Robin A. L.; Weinreb R. N.; Crawford K. and Shaw B., Drugs. 41 (4), p. 514-32 (1991).
The topical use of prostaglandins in treating elevated IOP and glaucoma has been found to be effective in primates and in some clinical studies to a greater extent than most currently used therapeutic agents by topical administration to the eye. U.S. Pat. No. 4,599,353 to Bito describes the use of prostaglandins preferably PGE.sub.2 and PGF.sub.2.alpha. for topical treatment of glaucoma. U.S. Pat. No. 4,994,274 to Chan, et al. describes certain 11, 15-diacyl derivatives of prostaglandins for use in lowering IOP. European Published Application No. 544899 describes 13,14-di:hydro-15(R)-17-phenyl 18,19,20-trinor PGF.sub.2.alpha. esters which are useful in treating elevated IOP. In contrast to the miotics, prostaglandins are believed to lower IOP by increasing the outflow of aqueous humor via the uveoscleral route. In addition, prostaglandins may possibly have other effects in the eye, such as enhancing vascular support of ocular tissues; however, there is no understanding of that mechanism at this time.
All six types of therapeutic agents have potentially serious side effects: miotics such as pilocarpine can cause blurring of vision and other visual side effects which may lead either to decreased patient compliance with the dosing regimen or to termination of therapy; carbonic anhydrase inhibitors can also cause serious side effects which affect patient compliance and/or necessitate the withdrawal of treatment; at least one beta-blocker, timolol, has increasingly become associated with serious pulmonary side effects attributable to its effect on .beta..sub.2 receptors in pulmonary tissue; and prostaglandins often produce hyperemia and edema of the conjunctiva, resulting in redness and hyperesthesia of the eye, which may affect patient compliance. In addition to these side effects, a therapy regimen which includes the use of two or more pharmaceutical compositions containing drugs selected from two or more of the above-cited classes requires the patient to apply the compositions to the affected eye(s) in separate, spaced dosages, several times per day. Patient compliance with such complicated dosage regimens can be very poor, particularly in elderly patients. Since the majority of glaucoma patients are elderly, problems with patient compliance are significant considerations to the prescribing physician.
In light of the foregoing circumstances, it is clear that a need exists for new, more potent anti-glaucoma compositions which avoid or reduce the above-cited side effects, while increasing patient compliance. The present invention is directed to such uses and compositions.